WO2025140381A1 - Compound composition of adapalene and dapsone, preparation method therefor, and use thereof - Google Patents

Abstract

The present disclosure belongs to the field of pharmaceutical formulations, and particularly relates to a compound composition of adapalene and dapsone for topical dermal use, a preparation method therefor, and use thereof. The composition of the present disclosure has at least one of the following excellent characteristics: high solubility of drug active ingredients in a carrier, small particle size of drug particles, stable particle size, good skin absorption, high in-vitro release efficiency, small particle size of composition oil drops, good stability, good therapeutic effect, small skin irritation, and good placement stability. The composition of the present disclosure can be directly used as a formulation, or can be further prepared into formulations of different dosage forms after other carriers are added.

Description

A compound composition of adapalene and dapsone, and preparation method and use thereof

Citation of Related Applications

This application claims all rights and interests of the invention patent application with application number 202311832033.8 filed with the State Intellectual Property Office of the People's Republic of China on December 28, 2023, and incorporates its entire contents into this application by reference.

Technical Field

The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a compound composition of adapalene and dapsone for topical skin application, a preparation method and use thereof.

Technical Background

Adapalene and dapsone are commonly used drugs for treating acne. Currently, the marketed products of adapalene include 0.1% and 0.3% gels and 0.1% creams, and the marketed products of dapsone include 5% and 7.5% gels.

Adapalene is a drug that is poorly soluble in water and oil. Due to its strong hydrophobicity, adapalene has low solubility in the matrix and is often dispersed in the gel matrix in a crystalline state, resulting in poor drug absorption and bioavailability. Relevant studies have shown that whether it is used as a gel or cream, the absorption rate of adapalene is very low, and it is easy to cause skin allergies and irritation. In addition, adapalene creams also have the problem of poor skin comfort.

The dapsone gel on the market has problems with storage instability and large particle size. After long-term storage, the particle size of the dapsone product in the gel gradually increases, affecting the stability of the product and causing a gritty feeling when used. In addition, the unstable particle size in topical preparations may lead to significant changes in its release and absorption rate during use, which is not conducive to the drug's efficacy.

Therefore, the known topical products of dapsone and adapalene for treating acne have their own problems, such as low solubility of the drug in the carrier, large particle size, particle size growth during storage, poor stability and poor skin absorption, etc. At present, there is still a need to develop a topical product to solve the above problems and achieve better stability, compliance and bioavailability, etc.

Summary of the invention

In order to prepare an external acne product with good drug solubility, suitable and stable particle size and good bioavailability, the present invention discloses a compound composition of adapalene and dapsone. The composition has at least one of the following excellent characteristics: high solubility of the active ingredient in the carrier, small drug particle size, stable particle size, good skin absorption, high in vitro release efficiency, small oil droplet size of the composition, good stability, good therapeutic effect, low skin irritation and good storage stability. The composition disclosed in the present invention can be used directly as a preparation, or can be further prepared into preparations of different dosage forms after adding other carriers.

In one aspect of the present disclosure, a compound composition of adapalene and dapsone is provided, which comprises, by total weight of the composition, 1%-15% of dapsone, 0.05%-0.5% of adapalene, 0.25%-20% of a carboxylic acid ester oily solvent, 0.5%-20% of a polyoxyethylene nonionic surfactant, 5%-50% of diethylene glycol monoethyl ether, and other pharmaceutically acceptable carriers.

In a preferred technical solution of the present disclosure, the composition comprises 0.25-15% of a carboxylic acid ester oily solvent based on the total weight of the composition.

In some embodiments, the composition comprises 0.25%-10%, 0.25%-5%, 0.25%-4%, 0.25%-3%, 0.25%-2%, 0.25%-1%, 0.5%-10%, 0.5%-5%, 0.5%-1%, 1%-10%, 1%-5%, 5%-10% or 10%-15% of a carboxylic acid ester oily solvent based on the total weight of the composition.

In some embodiments, the composition comprises 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15% of a carboxylic acid ester oily solvent based on the total weight of the composition.

In the preferred technical solution of the present disclosure, the carboxylate oily solvent is selected from any one of monocarboxylate, dicarboxylate, tricarboxylate or a mixture thereof; preferably, the oily solvent is monocarboxylate.

In some embodiments, the monocarboxylic acid ester is selected from any one of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, isopropyl palmitate, lauryl lactate, isopropyl myristate, ethyl oleate, ethyl linoleate, glyceryl monolinoleate, glyceryl monostearate, glyceryl monooleate, or a mixture thereof; the dicarboxylic acid ester is selected from any one of propylene glycol dicaprylate, diisopropyl adipate, diethyl sebacate, propylene glycol dicaprate, and di-n-butyl adipate, or a mixture thereof; the tricarboxylic acid ester is selected from any one of medium chain triglycerides, glyceryl triacetate, and caprylic capric triglyceride, or a mixture thereof;

Furthermore, the carboxylic acid ester oily solvent is selected from any one of propylene glycol monocaprylate and propylene glycol monolaurate or a mixture thereof.

In some embodiments, the carboxylic acid ester oily solvent is propylene glycol monocaprylate.

In some embodiments, the propylene glycol monocaprylate is the commercially available product Capryol.

In some embodiments, the propylene glycol monocaprylate is the commercially available product Capryol 90, which is a mixture of propylene glycol monoester and propylene glycol diester with a ratio of >90% monoester and <10% diester.

In some embodiments, the carboxylic acid ester oily solvent is propylene glycol monolaurate.

In some embodiments, the propylene glycol monolaurate is a commercially available product of the Lauroglycol series.

In some embodiments, the propylene glycol monolaurate is the commercially available product Lauroglycol 90, which is a mixture of propylene glycol monoester and propylene glycol diester with a ratio of >90% monoester and <10% diester.

In a preferred technical solution of the present disclosure, the composition comprises 0.5-15% of a polyoxyethylene nonionic surfactant based on the total weight of the composition.

In some embodiments, the composition comprises 0.5-10%, 0.5%-5%, 0.5%-4%, 0.5%-3%, 0.5%-2%, 0.5%-1%, 1%-10%, 1%-5%, 5%-10% or 10%-15% of a polyoxyethylene nonionic surfactant based on the total weight of the composition.

In some embodiments, the composition comprises 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14.%, 14.5%, 15% of a polyoxyethylene nonionic surfactant based on the total weight of the composition.

In the preferred technical scheme of the present invention, the polyoxyethylene nonionic surfactant is selected from any one of polyoxyethylene castor oil, fatty alcohol polyoxyethylene ether, polyol polyoxyethylene ether fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester and fatty amine polyoxyethylene ether, or a mixture thereof.

Furthermore, the polyoxyethylene nonionic surfactant is polyoxyethylene castor oil.

In some embodiments, the polyoxyethylene castor oil is selected from any one of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil or a mixture thereof.

Furthermore, the polyoxyethylene castor oil is selected from any one of polyoxyethylene 35 castor oil and polyoxyethylene 40 hydrogenated castor oil or a mixture thereof.

In some embodiments, the polyoxyethylene nonionic surfactant is polyoxyethylene 35 castor oil.

In some embodiments, the polyoxyethylene nonionic surfactant is polyoxyethylene 40 hydrogenated castor oil.

In a preferred technical solution of the present disclosure, the composition comprises 10%-50% of diethylene glycol monoethyl ether, and further 15%-45%, based on the total weight of the composition.

In some embodiments, the composition comprises 20%-45%, 20%-40%, 20%-35%, 20%-30%, 25%-45%, 25%-40%, 25%-35%, 30%-45%, 30%-40%, 35%-45% or 40%-45% of diethylene glycol monoethyl ether by total weight of the composition.

In some embodiments, the composition comprises 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% of diethylene glycol monoethyl ether by total weight of the composition.

In the preferred technical solution of the present disclosure, the composition comprises 2% to 12% of dapsone based on the total weight of the composition;

In some embodiments, the composition comprises, by weight of the total composition, 2%-11%, 2%-10%, 2%-9%, 2%-8%, 2%-7%, 2%-6%, 2%-5%, 2%-4%, 2%-3%, 3%-11%, 3%-10%, 3%-9%, 3%-8%, 3%-7%, 3%-6%, 3%-5%, 3%-4%, 4%-11%, 4%-10%, 4%-9.0%, 4%-8 %, 4%-7%, 4%-6%, 5%-11%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-11%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-11%, 7%-10%, 7%-9%, 7%-8%, 8%-11%, 8%-10%, 8.0%-9%, 9%-11%, 9%-10%, or 10%-11% dapsone.

In some embodiments, the composition comprises 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5% or 12% dapsone by total weight of the composition.

In some embodiments, the composition comprises 0.05%-0.4%, 0.05%-0.3%, 0.05%-0.2%, 0.05%-0.1%, 0.1%-0.4%, 0.1%-0.3%, 0.1%-0.2%, 0.2%-0.4%, 0.2%-0.3%, or 0.3%-0.4% adapalene based on the total weight of the composition.

In some embodiments, the composition comprises 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5% adapalene by total weight of the composition.

In some embodiments, the content of dapsone and adapalene in the composition is 7.5% and 0.1%, 6.0% and 0.1%, 5.0% and 0.1%, 7.5% and 0.15%, 6.0% and 0.15%, 5.0% and 0.15%, 7.5% and 2.0%, 6.0% and 2.0%, 5.0% and 2.0%, 7.5% and 3.0%, 6.0% and 3.0%, 5.0% and 3.0%, 12% and 0.3% or 3% and 0.075%, respectively, based on the total weight of the composition.

In the preferred technical solution of the present disclosure, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent in the composition is ≥1:1 or >1:1.

Furthermore, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent is ≤5:1, such as ≤4:1 or ≤3:1.

In some embodiments, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent is 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1 or 4.5:1.

In a preferred technical solution of the present disclosure, the other pharmaceutically acceptable carrier comprises a crystallization inhibitor, and the composition comprises 0.5%-4% of the crystallization inhibitor based on the total weight of the composition.

In some embodiments, the composition comprises 0.5%-3.5%, 0.5%-3%, 0.5%-2.5%, 0.5%-2%, 0.5%-1.5%, 1%-3.5%, 1%-3%, 1%-2.5%, 1%-2%, 1.5%-3.5%, 1.5%-3%, or 1.5%-2.5% of a crystallization inhibitor based on the total weight of the composition.

In some embodiments, the composition comprises 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, or 4% of a crystallization inhibitor, based on the total weight of the composition.

Furthermore, the crystallization inhibitor is selected from any one of polyvidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl cellulose (HPC) or a combination thereof.

In some embodiments, the crystallization inhibitor is PVP.

Furthermore, the polyvidone (PVP) is selected from any one of PVP-K12, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP K-90 or a combination thereof.

In some embodiments, the crystallization inhibitor is PVP-K30.

In a preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier further comprises a polymer copolymer emulsifier. Based on the total weight of the composition, the composition comprises 0.05-6% of the polymer copolymer emulsifier.

Furthermore, the composition comprises 0.05%-1% of a high molecular weight copolymer emulsifier based on the total weight of the composition.

In some embodiments, based on the total weight of the composition, the composition comprises 0.05%-0.9%, 0.05%-0.8%, 0.05%-0.7%, 0.05%-0.6%, 0.05%-0.5%, 0.05%-0.4%, 0.05%-0.3%, 0.05%-0.2%, 0.05%-0.1%, 0.1%-0.9%, 0.1%-0.8%, 0.1%-0.7%, 0.1%-0.6%, 0.1%-0.5%, 0.1%-0.4%, 0.1%-0.3%, 0.1%-0.2%, 0.2%-0.9%, 0.2%-0.8%, 0.2%-0.7%, 0.2%-0.6%, 0.2 %-0.5%, 0.2%-0.4%, 0.2%-0.3%, 0.3%-0.9%, 0.3%-0.8%, 0.3%-0.7%, 0.3%-0.6%, 0.3%-0.5%, 0.3%-0.4%, 0.4%-0.9%, 0.4%-0.8%, 0.4%-0.7%, 0.4%-0.6%, 0.4%-0.5%, 0.5%-0.9%, 0.5%-0.8%, 0.5%-0.7%, 0.5%-0.6%, 0.6%-0.9%, 0.6%-0.8%, 0.6%-0.7%, 0.7%-0.9%, 0.7%-0.8% or 0.8%-0.9% of a high molecular weight copolymer emulsifier.

Further, based on the total weight of the composition, the composition comprises 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95% or 1% of the high molecular weight copolymer emulsifier.

Furthermore, the high molecular weight copolymer emulsifier is a carbomer copolymer.

Furthermore, the carbomer copolymer is an acrylic acid (ester)/(C10-30) alkyl acrylate cross-linked copolymer.

In some embodiments, the acrylic acid (ester)/(C10-30) alkanol acrylate cross-linked copolymer is selected from any one of the commercially available products PEMULEN TR-1, PEMULEN TR-2 and PEMULEN EZ-4U or a combination thereof.

In some embodiments, the polymer copolymer emulsifier is PEMULEN TR-1.

In a preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier further comprises a thickener, and based on the total weight of the composition, the composition comprises 0.1%-4% of the thickener.

Furthermore, the thickener is selected from any one of polyacrylamide and carbomer homopolymer or a combination thereof.

In some embodiments, the polyacrylamide is an acrylamide/sodium acryloyldimethyl taurate copolymer/isohexadecane/polysorbate 80 mixture (Sepineo P600).

In some embodiments, the carbomer homopolymer is carbomer 981.

Furthermore, the thickener is selected from any one of Sepineo P600 and Carbomer 981 or a combination thereof.

In some embodiments, the thickener is a combination of Sepineo P600 and Carbomer 981.

In some embodiments, the composition comprises 1%-3% Sepineo P600 and 0.1%-1% Carbomer 981, based on the total weight of the composition.

In some embodiments, the composition comprises 1%, 1.5%, 2%, 2.5% or 3% Sepineo P600, based on the total weight of the composition.

In some embodiments, the composition comprises 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% Carbomer 981 based on the total weight of the composition.

In some embodiments, the composition comprises 1.5% Sepineo P600 and 0.2% Carbomer 981, based on the total weight of the composition.

In a preferred technical solution of the present disclosure, the solubility of adapalene in the composition is at least 10 times higher than its solubility in water at the same temperature, for example, more than 100 times higher.

In a preferred technical solution of the present disclosure, the oil droplet diameter of the composition is ≤300 nm; for example, ≤250 nm.

In some embodiments, the oil droplet size of the composition is ≤ 240 nm, 220 nm, 200 nm, 180 nm, 160 nm, 140 nm, 120 nm, 100 nm, 80 nm, 60 nm, 50 nm, 40 nm, or 30 nm.

In a preferred technical solution of the present disclosure, the transparency of the composition is not less than 50%, for example, not less than 80%.

In the preferred technical solution of the present disclosure, when the content of Adapalene is 0.10% of the total weight of the composition, at least 10% of the Adapalene is in a dissolved state.

In the preferred technical solution of the present disclosure, when the content of dapsone is 7.5% of the total weight of the topical pharmaceutical composition for skin application, at least 50% of the dapsone is in a dissolved state.

In the preferred technical solution of the present disclosure, the composition can be directly applied to the skin, or other pharmaceutically acceptable carriers can be added to prepare other local pharmaceutical preparations.

In the preferred technical solution of the present disclosure, the composition is an emulsion or latex.

In some embodiments, the composition is an emulsion, such as a microemulsion.

In some embodiments, the composition is a latex, such as a microemulsion gel.

In the preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier may further include any one or a combination of a preservative, an antioxidant, a chelating agent and a pH adjuster.

In the technical solution provided by the present disclosure, the stability of the composition or the local pharmaceutical preparation prepared therefrom is further improved by adding preservatives, antioxidants, chelating agents and pH regulators, and the specific amount added is added according to the commonly used concentration range of excipients.

In some embodiments, the preservative is selected from any one of methylparaben (methylparaben), benzyl alcohol, sodium benzoate, ethylparaben, propylparaben, potassium sorbate, phenoxyethanol, or a combination thereof.

In some embodiments, the preservative is methylparaben (methylparaben).

In some embodiments, the antioxidant comprises any one or a combination thereof selected from butyl hydroxyanether (BHA), butyl hydroxytoluene (BHT), propyl gallate and α-tocopherol.

In some embodiments, the antioxidant is butylated hydroxytoluene (BHT).

In the preferred technical scheme of the present invention, the chelating agent is selected from any one or a combination of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-di(o-hydroxyphenyl)acetic acid (EDDHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethylenediamine-di(o-hydroxy-p-methylphenyl)acetic acid (EDDHMA) and ethylenediamine-di(5-carboxy-2-hydroxyphenyl)acetic acid (EDDCHA).

In some embodiments, the chelating agent is edetate disodium.

In a preferred technical solution of the present disclosure, the pH adjuster comprises any one selected from sodium hydroxide and triethanolamine or a combination thereof.

In some embodiments, the pH adjuster is sodium hydroxide.

In the preferred technical solution of the present disclosure, the pH range of the composition is between 5.0-7.0.

In some embodiments, the composition has a pH range of 5.0-6.5.

In some embodiments, the composition has a pH range of 5.0-6.0.

Another aspect of the present disclosure is to provide a method for preparing a compound composition of adapalene and dapsone, the preparation method comprising the following steps:

1) preparing an oil phase: adding dapsone and adapalene to a mixed solution of a carboxylic acid ester oily solvent, a polyoxyethylene nonionic surfactant and diethylene glycol monoethyl ether to form an oil phase;

2) preparing the aqueous phase: uniformly dispersing other pharmaceutically acceptable carriers in water and mixing them to form an aqueous phase; or directly using water as the aqueous phase;

3) Emulsification: Add the oil phase of step 1) to the water phase of step 2), adjust the pH to 5.0-6.0, mix well, and add water to 100%.

According to a preferred technical solution of the present disclosure, the other pharmaceutically acceptable carrier in step 2) is any one of a polymer emulsifier, a thickener and a crystallization inhibitor or a combination thereof.

Furthermore, in the step 2), other pharmaceutically acceptable carriers are polymer emulsifiers, thickeners and crystallization inhibitors.

Furthermore, in the step 2), a thickener may be added after the polymer copolymer emulsifier is added.

Furthermore, in the step 2), a crystallization inhibitor may be added before adding the high molecular weight copolymer emulsifier.

According to a preferred technical solution of the present disclosure, any one or a combination of a penetration enhancer, an antioxidant, a preservative and a chelating agent may be added to the steps 1) and/or 2).

Another aspect of the present disclosure provides a use of a compound composition of adapalene and dapsone in preparing a medicament for treating skin diseases.

According to an embodiment of the present disclosure, the skin disease is acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, or prickly heat.

Further, the skin disease is acne vulgaris.

According to an embodiment of the present disclosure, the acne vulgaris is mild, moderate, moderately severe or severe acne;

Moderate or moderately severe acne is preferred.

Another aspect of the present disclosure provides a use of a compound composition of adapalene and dapsone in preparing a pharmaceutical preparation for topical administration.

According to an embodiment of the present disclosure, the topically administrable pharmaceutical preparation is selected from an emulsion, an emulgel or a cream.

Another aspect of the present disclosure provides a method for treating skin diseases, comprising administering a therapeutically effective amount of the compound composition of adapalene and dapsone of the present disclosure to a subject in need thereof.

According to an embodiment of the present disclosure, the skin disease is acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, or prickly heat.

According to an embodiment of the present disclosure, the skin disease is acne vulgaris.

In the present disclosure, acne vulgaris can occur on the face, chest, back and sometimes even more extensively. Depending on the severity, acne vulgaris can be mild, moderate or severe, with mild acne usually classified by the appearance of blackheads and whiteheads, but can also include papules and pustules; moderate acne is usually characterized by the appearance of more painful, deep, inflamed lesions, which may lead to scarring; severe acne is characterized by the appearance of deep inflammatory lesions, including cysts and nodules, which may be painful and can produce scars.

The topical pharmaceutical composition for skin application disclosed herein has the following beneficial effects:

1) The present invention adopts a combination of a specific type of oily solvent, a surfactant and a co-surfactant to prepare a clear, non-stratified, transparent adapalene and dapsone compound composition microemulsion system with good stability. And the adapalene and dapsone compound latex prepared according to the above microemulsion system is placed under 25±2℃/60±5%RH, 30±2℃/65%±5%RH and 40±2℃/75%±5%RH conditions, and its properties, pH, viscosity, particle size, active ingredient content and related substances can be kept at least 12 months before and after placement without obvious changes, and the stability is good.

2) In the composition provided by the present disclosure, the solubility of adapalene in the composition carrier is increased by more than 100 times compared with that in water, which is beneficial to improving the absorption of adapalene.

3) In the composition provided by the present invention, the inventors, after multiple screenings, surprisingly found that when the weight ratio of the polyoxyethylene nonionic surfactant to the oily solvent is controlled to be greater than 1:1, even if the dosage of the polyoxyethylene nonionic surfactant and the oily solvent is relatively low, a clear, non-stratified, and transparent microemulsion system can still be prepared, while reducing the stickiness, odor, and irritation of the system.

4) A crystallization inhibitor is added to the composition provided by the present disclosure, which greatly reduces the particle size of the drug particles, inhibits the growth of the drug particles, and reduces the grittiness felt by patients during application.

5) In the composition provided by the present disclosure, the particle size of the oil droplets is less than 300 nm, which is conducive to the rapid absorption of the active ingredients of the medicine by the skin.

6) In the composition provided by the present disclosure, the release rate of dapsone can be increased by 1.5 times compared with the prior art, and the amount of skin absorption in the epithelium and dermis can be increased by 1.9 times compared with the prior art, which is beneficial to the improvement of drug efficacy.

7) The composition provided by the present disclosure has good therapeutic effect on diseases such as acne.

8) The composition provided by the present disclosure can reduce the irritation of drugs to the skin and has good tolerance and safety.

9) The composition provided by the present disclosure is non-greasy and easy to spread.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a PLM spectrum of the E15 sample in Experimental Example 2;

FIG2 is a PLM spectrum of the E2 sample in Experimental Example 2;

FIG3 is a PLM spectrum of the E11 sample in Experimental Example 2;

FIG4 is a PLM spectrum of the R2 sample in Experimental Example 2;

FIG5 is an overlay of XRD patterns of samples E2, E11, E15 and R2 in Experimental Example 2;

FIG6 is a graph showing the change rate of total skin lesions in rabbit ears in each administration group at 11 days and 14 days compared with the baseline in Experimental Example 5;

FIG. 7 shows the change rate of inflammatory lesions in the ears of rabbits in each administration group at 11 days and 14 days of administration compared with the baseline in Experimental Example 5.

DETAILED DESCRIPTION

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

In the present disclosure, an emulsion is an emulsified system formed by two immiscible phases through a specific emulsifier (surfactant), in which fine droplets of one liquid are uniformly dispersed in another liquid, the former is called a dispersed phase, and the latter is called a continuous phase. It is customary to refer to the organic liquid constituting the emulsion as "oil (O)", and oil (O) dispersed in water (W) is called an oil-in-water emulsion (O/W); conversely, it is called an oil-in-water emulsion (W/O). In order to improve the solubility and transdermal absorption of hydrophobic drugs, a uniform and stable O/W type emulsion is formed by dissolving the raw drug in oil phase droplets, and the oil droplets are dispersed in the water phase. An emulsion with an oil droplet size of less than 300nm is called a microemulsion.

In the present disclosure, latex or latex agent is an emulsion type gel. Gel or gel agent refers to a thick liquid or semi-solid preparation with gel properties made from a raw drug and an excipient capable of forming a gel. Latex or latex agent refers to a thick liquid or semi-solid preparation with gel properties made from a raw drug dissolved/dispersed in oil phase droplets, which are then dispersed in an excipient capable of forming a gel.

In the present disclosure, cream or ointment is a uniform semi-solid external preparation made by mixing raw drug with oily or water-soluble matrix. Cream can be divided into oil-in-water cream and water-in-oil cream due to different matrices.

In the present disclosure, nonionic surfactants are surfactants that do not dissociate into ions in water and are insensitive to pH changes.

In the present disclosure, "poorly water-soluble drugs" refer to drugs that are known to be applicable in the medical field and have low solubility in water relative to their effective dosage. Specifically, it refers to drugs for which the amount of solvent (amount of water) required to dissolve 1g or 1mL of solute is more than 100mL (concentration is less than 1%), preferably more than 1000mL (concentration is less than 0.1%), and more preferably more than 10000mL (concentration is less than 0.01%).

In this disclosure, "pharmaceutically acceptable carrier" refers to any pharmaceutically acceptable ingredient known to those skilled in the art, which is generally regarded as an inactive ingredient.

In the present disclosure, the content of adapalene is detected by HPLC, mobile phase A: 0.05% TFA/acetonitrile (95%), mobile phase B: water (5%), detection wavelength: 270 nm.

Screening Example 1: Screening of oily solvents, surfactants and co-surfactants

(1) Solubility of adapalene in various media.

Solubility test method: Take 2-3 mL of the medium in Table 1, add excess adapalene to obtain a suspension, stir at room temperature for 24 hours, filter, and take the clarified filtrate for testing.

In the present disclosure, when the solubility of adapalene in the medium reaches about 400 μg/ml or more, it is considered that the solubility requirement can be met.

The results are shown in Table 1:

Table 1

^* Note: Polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol (15)-hydroxystearate are solid or semi-solid at room temperature and need to be dissolved in diethylene glycol monoethyl ether before measuring the solubility of adapalene in the mixed medium.

The results in Table 1 show that in oily solvents, the solubility of adapalene in propylene glycol monocaprylate, propylene glycol monolaurate, diisopropyl adipate and diethyl sebacic acid is all above 400 μg/ml, which can meet the solubility requirements.

Among surfactants, the solubility of adapalene in diethylene glycol monoethyl ether/polyoxyethylene (35) castor oil (2/1), diethylene glycol monoethyl ether/polyoxyethylene (40) hydrogenated castor oil (2/1), and diethylene glycol monoethyl ether/polyethylene glycol (15)-hydroxystearate (2/1) is above 3000 μg/ml, the solubility in caprylic capric acid macrogol glyceride is above 1000 μg/ml, and the solubility in monoolein glyceryl is close to 400 μg/ml, all of which can meet the solubility requirements;

Among the co-surfactants, the solubility of adapalene in diethylene glycol monoethyl ether is above 2000 μg/ml, which can meet the solubility requirement.

(2) Further screening of surfactant types

Using propylene glycol monocaprylate as the oily solvent and diethylene glycol monoethyl ether as the co-surfactant, the appearance, transparency, stability and solubility of adapalene in the system formed by different surfactant combinations in Table 2 were investigated.

Test method:

At room temperature, 5% propylene glycol monooctanoate, 30% diethylene glycol monoethyl ether, and 15% surfactant were added to a beaker, stirred and mixed, and purified water was added dropwise to the beaker while stirring (to 100%) to form a system sample. The following parameters were evaluated, and the results are shown in Table 2.

a) Appearance: Let it stand and observe whether it is clear and has layers.

b) Transparency: For samples that did not delaminate after standing at room temperature for one day, the transparency of the composition was tested by UV-Vis spectroscopy (transmittance at 650 nm (with water as blank)).

c) Stability: For samples that have not been stratified after being placed at room temperature for one day, centrifuge at 8000 rpm for 15 min to observe whether stratification occurs.

d) Solubility of adapalene: Take 2-3 mL of sample, add excess adapalene to obtain a suspension, stir at room temperature for 24 h, filter, and take the clear filtrate for testing.

Table 2

The results in Table 2 show that when the oily solvent is propylene glycol monocaprylate and the co-surfactant is diethylene glycol monoethyl ether, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil are selected as surfactants, the obtained samples have a clear and transparent appearance, a transparency of more than 99%, good phase stability, and are not prone to oil-water separation, and adapalene has high solubility; while when caprylic capric acid polyethylene glycol glyceride, monooleic acid glyceride and polyethylene glycol (15)-hydroxystearate are selected as surfactants, the obtained samples are turbid, indicating that the droplet size is large, oil-water separation is prone to occur, and there is a risk of poor stability.

(3) Further screening of oily solvent types

Using diethylene glycol monoethyl ether as a co-surfactant and polyoxyethylene (35) castor oil as a surfactant, the appearance, clarity, stability and solubility of adapalene of the systems formed by different oily solvents in Table 3 were investigated.

Test method:

At room temperature, add 15% polyoxyethylene (35) castor oil, 30% diethylene glycol monoethyl ether and 5% oily solvent into a beaker and stir to mix. Take pure water and add it dropwise into the beaker while stirring (make up to 100%) to form a system sample, which is evaluated by the following parameters.

a) Appearance: Let the sample stand and observe whether it is clear and stratified.

b) Transparency: For samples that did not delaminate after being stored at room temperature for one day, their transparency (transmittance at 650 nm (with water as blank)) was tested by UV-Vis spectroscopy.

c) Stability: For samples that have not been stratified after being placed at room temperature for one day, centrifuge at 8000 rpm for 15 min to observe whether stratification occurs.

d) Solubility of adapalene: 2-3 mL of different samples were taken, and an excess of adapalene was added to obtain a suspension, which was stirred at room temperature for 24 h, filtered, and the clear filtrate was taken for detection.

The results are shown in Table 3.

Table 3

The results in Table 3 show that when the co-surfactant is diethylene glycol monoethyl ether and the surfactant is polyoxyethylene (35) castor oil, propylene glycol monocaprylate and propylene glycol monolaurate are selected as the oily solvents, respectively, and the obtained samples have a transparent and clear appearance, good stability, a transparency of more than 96%, and a high solubility of adapalene; while when diisopropyl adipate, diethyl sebacic acid, medium-chain triglycerides and soybean oil are used as the oily solvents, the obtained samples are turbid, indicating that the droplet size in the system is large, oil-water separation is prone to occur, and there is a risk of poor stability.

Screening Example 2: Investigation of the ratio of oily solvent and nonionic surfactant

According to the investigation results of Screening Example 1, this screening example uses propylene glycol monocaprylate as an oily solvent, diethylene glycol monoethyl ether as a co-surfactant and polyoxyethylene (35) castor oil as a surfactant to prepare a composite composition of adapalene and dapsone, and investigates the effects of compositions formed by different proportions of oily solvent and surfactant on the appearance, clarity, stability of droplets and the solubility of adapalene.

Test method:

At room temperature, according to the prescription in Table 4, adapalene, dapsone, propylene glycol monocaprylate, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether were mixed and stirred to obtain an oil phase solution, and then purified water was added to the oil phase solution and stirred to obtain a compound composition of adapalene and dapsone.

Table 4

The composition samples prepared above were evaluated by the following parameters.

Appearance: After the composition is left to stand at room temperature for 1 day, observe whether it is turbid or separated into layers.

Stability: For the composition sample that has not been separated after being placed at room temperature for one day, centrifuge it at 8000 rpm for 15 min to observe whether it is separated.

Transparency: For the composition sample that was not delaminated after standing at room temperature for 1 day, the transparency of the composition was tested by UV-Vis spectroscopy (transmittance at 650 nm (with water as blank)).

Oil droplet diameter: Take a sample of the composition and measure it three times using a laser particle size analyzer to calculate the average value.

pH: Take a sample of the composition and measure it three times using a pH meter to calculate the average value.

The results are shown in Table 5.

Table 5

The results in Table 5 show that: 1) when the ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is greater than 1:1, such as 1.5:1, 2:1 or 3:1 (M2, M3, M6, M10-M15), the prepared composition is a colorless and transparent microemulsion with an oil droplet size of less than 100 nm and good stability without turbidity or stratification.

2) When the ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is 1:1 and the content is 15% or 10% (M9, M5), the prepared composition is a colorless and transparent microemulsion with an oil droplet size of less than 250nm and good stability without turbidity or stratification.

3) When the ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is 1:1 and the content accounts for 5% (M1), the prepared composition is milky white and stratification occurs during the storage process.

4) When the ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is less than 1:1 (M4, M7, M8), the prepared composition is milky white and stratification occurs during storage.

In summary, when the mass ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is greater than 1:1, or when the mass ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is 1:1 and a relatively high content of surfactant is maintained at the same time, a composite composition of adapalene and dapsone with good stability, high transparency and small oil droplet size can be obtained; when the mass ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is 1:1 and the content of surfactant is relatively low, or when the mass ratio of polyoxyethylene (35) castor oil/propylene glycol monocaprylate is less than 1:1, or, the obtained composition is milky white and turbid, and stratification will occur, with poor stability.

Embodiment 1: the preparation of the compound composition of adapalene and dapsone (latex)

According to the prescriptions in Table 6 and Table 7, the latex of the present disclosure was prepared.

Table 6

Table 7

According to the prescriptions in Tables 6 and 7:

a) Preparation of aqueous phase:

Take an appropriate amount of purified water into the water phase bucket, add disodium edetate, and stir until dissolved; then add Carbomer 981 and PEMULEN TR-1, stir to disperse them evenly, and obtain an aqueous phase solution.

b) Preparation of oil phase:

Take diethylene glycol monoethyl ether into the oil phase barrel, add PVP-K30, methyl hydroxybenzoate and butylated hydroxytoluene, and stir until dissolved; then add dapsone, stir until dissolved, and obtain an oil phase solution 1 containing dapsone.

Add polyoxyethylene (35) castor oil to another oil phase barrel, heat and stir at 50-60°C to obtain a yellow clear liquid, then add propylene glycol monocaprylate and stir until mixed evenly to obtain oil phase solution 2.

The oil phase solution 2 is added to the oil phase solution 1 and stirred evenly; then adapalene is added and stirred to obtain a suspension oil phase solution containing the active ingredient.

c) Preparation of sodium hydroxide solution

Mix sodium hydroxide and an appropriate amount of purified water and stir until fully dissolved.

d) Mixing and emulsification

Add the aqueous phase solution to the suspended oil phase solution, stir and homogenize; then add sodium hydroxide solution and SEPINEO P 600, stir and homogenize to obtain the latex agent disclosed herein.

Comparative Example 1: Preparation of gel

Adapalene gel R1 was prepared according to Example 1 of US7838558, and dapsone gel R2 was prepared according to Example 1 in CN105246457B. The specific prescription is shown in Table 8.

Table 8

Preparation method of comparative example R1:

According to the prescription in Table 8, phenoxyethanol, methyl paraben, poloxamer and disodium edetate were added to water to dissolve, and then carbomer was added and mixed evenly to obtain an aqueous phase; adapalene was added to propylene glycol and mixed evenly to obtain an organic phase; the organic phase was slowly added to the aqueous phase under stirring, uniformly dispersed and homogenized to obtain the adapalene hydrogel of Comparative Example 1.

Preparation method of comparative example R2:

According to the prescription in Table 8, methyl parahydroxybenzoate was added into water to dissolve to obtain an aqueous phase; dapsone was added into diethylene glycol monoethyl ether and mixed evenly to obtain an organic phase; the organic phase was slowly added into the aqueous phase under stirring, and finally SEPINEO P600 was added, evenly dispersed and homogenized to obtain the dapsone hydrogel of Comparative Example 2.

Test Example 1: Comparative study of in vitro release and skin absorption.

The in vitro release and skin absorption of dapsone in the latex provided by the present disclosure (Examples E2 and E3) and the prior art hydrogel (Comparative Example R2) were compared.

Test method:

In vitro release: A vertical diffusion cell was used, and a solution of isopropanol: cyclodextrin: potassium dihydrogen phosphate: water (30:5:0.6:64.4) was used as the receiving medium for dapsone. PVDF was used as a filter membrane and fixed between the supply chamber and the receiving chamber of the diffusion cell. The diffusion cell was fixed in a transdermal absorption diffusion instrument, and an in vitro release experiment was performed at 32°C and 600 rpm. The content of dapsone in the diffusion cell was detected by HPLC, and the release rate of dapsone within 6 hours was calculated.

Skin absorption: A vertical diffusion cell was used, and a solution of isopropyl alcohol: cyclodextrin: potassium dihydrogen phosphate: water (30:5:0.6:64.4) was used as the receiving medium for dapsone. Pig skin was used as a filter membrane and fixed between the supply chamber and the receiving chamber of the diffusion cell. The diffusion cell was fixed in a transdermal absorption diffusion instrument, and a skin absorption experiment was performed at 32°C and 600 rpm. After 24 hours, the pig skin was removed, and the sample remaining on the surface of the pig skin was wiped off with a cotton swab, and the stratum corneum was peeled off with tape. Finally, the remaining epithelial and dermal tissues were cut into pieces, and the dapsone in the tissues was extracted with methanol. The content of dapsone was detected by HPLC, and the total absorption of dapsone in the epithelial and dermal tissues was calculated.

The results are shown in Table 9.

Table 9

The results in Table 9 show that the in vitro release rate of dapsone in the latex of the present invention is significantly higher than that in the hydrogel of the prior art, wherein the in vitro release rates of dapsone in Examples E2 and E3 are 1.2 times and 1.5 times that in Comparative Example R2, respectively. The skin absorption amount of dapsone in the latex of the present invention is significantly higher than that in the hydrogel, wherein the absorption amounts of dapsone in the epithelium and dermis in Examples E2 and E3 of the present invention are 1.9 times and 1.5 times that in Comparative Example R2, respectively.

Test Example 2: Comparative Study of Particle Size and Dispersion State

Optical microscopy (PLM) and X-ray diffractometer (XRD) were used to compare the particle size and dispersion state of the crystal particles in the latex of the present disclosure (Examples E2, E11, E15) and the prior art hydrogel (Comparative Example R2).

Test method:

The PLM spectrum was collected from an XPV-990E polarized light microscope; a small amount of sample was placed on a glass slide, covered with a cover slip, and placed on a stage for observation, photography, and particle size statistics.

XRD data were collected from a Bruker D8 Advance diffractometer; parameters were as follows: Cu target; wavelength Current and voltage: 40KV, 40mA; Angle range: 3-40°2θ.

The results are shown in Figures 1-5.

The results in Figures 1-4 show that in the latex examples E2 and E15 provided by the present disclosure containing PVP-K30, the drug particles have a small particle size (D90 <30 μm), and no large particles with a particle size exceeding 50 μm were found; in the latex example E11 provided by the present disclosure without PVP-K30, a small amount of large particles with a particle size exceeding 100 μm were found; and in the sulfone hydrogel preparation R2 that also does not contain PVPPK30, a large number of large particles with a particle size exceeding 50 μm and 100 μm were found.

The results in Figure 5 show that no crystal diffraction peaks appear in the latex examples E2 and E15 containing PVP-K30 provided by the present disclosure, indicating that the drug particles in the preparations are small in size and well dispersed; a crystal diffraction peak appears in the latex example E11 not containing PVP-K30 provided by the present disclosure, but the peak intensity is weak; and a strong dapsone crystal diffraction peak is found in the dapsone hydrogel preparation R2 not containing PVP-K30, indicating that the dapsone particles in the hydrogel are large in size and poorly dispersed.

Test Example 3: Skin touch test

Since the particle size of particles in topical preparations can affect the user experience of applying the product, the inventors of the present disclosure further investigated the skin feel of the latex examples E2, E11 and E15 and the hydrogel comparative example R2 of the present disclosure upon application.

The results show that: the latex examples E2 and E15 provided by the present disclosure containing PVP-K30 have no gritty feeling during the application process, the latex example E11 not containing PVP-K30 has a slight gritty feeling; and the sulfone hydrogel preparation comparative example R2 not containing PVP-K30 has an obvious gritty feeling during the application process.

It can be seen that adding PVP-K30 to the compound composition of adapalene and dapsone can inhibit the growth of drug particles, reduce the particle size, and reduce the grittiness produced during the application process.

Test Example 4: Stability Study

The latex provided by the present disclosure was subjected to a long-term (25±2°C/60±5%RH) stability test, and the following indicators were tested: appearance, pH, PLM particle size, viscosity, HPLC content and related substances. The results are shown in Tables 10-14.

Table 10

The results in Table 10 show that the properties and appearance of the latexes of Examples E2, E3 and E15 remained unchanged for 12 months when placed under 25±2°C/60±5%RH, respectively, and the stability was good.

Table 11

The results in Table 11 show that the latexes of Examples E2, E2 and E15 were placed under 25±2°C/60±5%RH for 1 month, and the pH did not change significantly, indicating good stability.

Table 12

Viscosity determination method: Method 1: Tested using a Brookfield viscometer, using a T-C (93) rotor, a rotation speed of 5 rpm, and a test time of 1 min. Method 2: Tested using a Brookfield viscometer, using a T-D (94) rotor, a rotation speed of 40 rpm, and a test time of 1 min.

The results in Table 12 show that the viscosity of the latex of Example E15 remained basically unchanged when placed under 25±2°C/60±5%RH for one month, and the stability was good.

Table 13

The results in Table 13 show that the particle size (D90) of the latex of Example E3 remained essentially unchanged after being placed under the conditions of 25±2°C/60±5%RH for 6 months.

Table 14

Notes: [1] Percentage of product labeled amount; [2] Percentage of total impurities;

The results in Table 14 show that the latexes of Examples E2, E3 and E15 were placed under 25±2°C/60±5%RH for 12 months, and the active ingredient content and related substance content remained unchanged, indicating good stability.

In summary, the latex prepared in the present invention is a white latex. When placed under 25±2°C/60±5%RH conditions, its properties, pH, viscosity, drug particle size (D90), active ingredient content and related substance content can remain unchanged for at least 12 months, and all quality indicators meet the product quality standards and have good stability.

In addition, the inventors of the present disclosure also studied the storage stability of the latex (Examples E2, E3 and E15) under the conditions of 40±2°C/75%±5%RH and 30±2°C/65%±5%RH, and also showed good stability.

Test Example 5: Comparative Study of Drug Efficacy

The rabbit ear acne model was used to compare the therapeutic effects of the latex of the present invention (Examples E15 and E16), the adapalene hydrogel of the prior art (Comparative Example R1) and the dapsone hydrogel (Comparative Example R2) on acne.

Test method:

Modeling: 2% coal tar was applied to the 2cm*2cm area of the right ear tube outlet of New Zealand white rabbits every day, 0.5-1ml/rabbit, for 18 consecutive days. On the 8th day, Propionibacterium acnes was injected intradermally in the right ear, 7-8 sites/rabbit, 30μL/site, once every other day, for a total of 6 injections. All rabbit ears were photographed and observed 24 hours after the last injection, and the number of acne, papules and pustules was counted.

Grouping: The animals after modeling were randomly divided into a model group, an Example E15 administration group, an Example E16 administration group, a Comparative Example R1 administration group, and a Comparative Example R2 administration group.

Drug administration: After grouping, drug administration began. 0.4 mL/rabbit/day of the test drug was applied to the rabbit ear model for 2 consecutive weeks.

The numbers of acne, papules and pustules in each group were counted before administration (Day 0), 11 days and 14 days after administration.

24 hours after the last administration, the right ear was removed and fixed with 4% paraformaldehyde, then routinely paraffin-embedded and sectioned, and HE-stained to observe the pathological morphological changes of ear tissue under a light microscope (including general observation indicators: keratin hyperplasia, thickening of the stratum spinosum, dilation of hair follicles, hyperplasia of sebaceous glands, inflammatory cell infiltration, and histological determination of experimental acne).

The results are shown in Figures 6 and 7.

The results show that after 11 days and 14 days of administration, the change rates of total skin lesions (acne + papules + pustules) and inflammatory skin lesions (papules + pustules) of the emulsions of the present invention (Examples E15 and E16) compared with the baseline are lower than those of dapsone hydrogel (Comparative Example R2) and adapalene hydrogel (Comparative Example R1), indicating that the therapeutic effects of the emulsions of the present invention on total acne lesions and inflammatory skin lesions are better than those of dapsone hydrogel and adapalene hydrogel in the prior art.

In addition, in terms of pathological structure, 14 days after administration, the latex of the present invention (Examples E15 and E16) was superior to the prior art sulfone hydrogel (Comparative Example R2) and adapalene hydrogel (Comparative Example R1) in improving the hyperkeratosis of the rabbit ear epidermis, keratinized material filling, hair follicle expansion, sebaceous gland hyperplasia, inflammatory cell infiltration, etc.

Test Example 6: Toxicity Study

The toxicity of the latex formulations of Example E19 (0.15% adapalene and 6% dapsone compound latex) and Example E20 (0.30% adapalene/12% dapsone compound latex) of the present disclosure was studied.

(1) Guinea pig active skin allergy test

Test method:

Grouping: British guinea pigs were randomly divided into a negative control group, a positive control group, a blank latex control group (without adapa and lindapsone, and the other components were the same as the drug-treated group), an Example E19 drug-treated group, and an Example E20 drug-treated group.

Dosage

Sensitization drug

Preparation before administration: Before administration, the skin on the left back of the guinea pig was depilated, and the prepared skin area was about 5 cm × 5 cm.

On the 1st, 8th and 15th days of the experiment, the negative control group was given sterile injection water percutaneously at 0.2 mL/mouse, the positive control group was applied with 1% 1-chloro-2,4-dinitrobenzene at 0.2 mL/mouse, and the other groups were applied with the corresponding test substance at 0.5 g/mouse. The mice were covered with cellophane (about 4 cm × 4 cm) and gauze, sealed and fixed with medical tape for about 6 hours, and then the dressing was removed.

Provocative drug administration

Preparation before administration: Before administration, the skin on the right back of the guinea pig was removed with a skin preparation area of approximately 5 cm × 5 cm;

On the 29th day of the experiment, the negative control group was given sterile injection water percutaneously at 0.2 mL/mouse, the positive control group was applied with 0.5% 1-chloro-2,4-dinitrobenzene at 0.2 mL/mouse, and the other groups were applied with the corresponding test substance at 0.5 g/mouse. The mice were covered with cellophane (about 4 cm × 4 cm) and gauze, sealed and fixed with medical tape for about 6 hours, and then the dressing was removed.

Observation score

Observation time: 1 hour (±30 minutes), 24 hours (±2 hours) after each sensitization and 1 hour (±30 minutes), 24 hours (±1 hour), 48 hours (±2 hours), and 72 hours (±2 hours) after each stimulation.

Observed animals: All surviving guinea pigs in each group;

Observation content: Score the skin observation at the administration site. Calculate the total score of each side of the skin at each inspection time point and the average score of the skin observation in the same dose group. After stimulation, the animal should also be observed for systemic allergic reactions such as asthma, unsteady standing or shock.

The results showed that, except for the positive drugs, no obvious skin and systemic allergic reactions occurred in the guinea pigs in each group, indicating that the latex agent disclosed in the present invention is non-allergenic.

(2) Long-term toxicity study in miniature pigs

Test method:

Grouping: Bama miniature pigs were randomly divided into a blank control group, a blank latex control group (without adapalene and dapsone, and the other components were the same as the drug-treated group), an Example E19 drug-treated group, and an Example E20 drug-treated group.

Dosage

Apply transdermally on the back, once a day for 28 days;

Preparation before administration: Before administration, remove the fur on the back of the miniature pigs and prepare the skin. The preparation area should be slightly larger than the application area of each animal. The frequency of skin preparation should be at least once a week. Before administration, mark the application area with a marker pen, pay attention to the skin condition, and avoid skin damage. Clean the administration site with drinking water before administration every 2 to 28 days, and wipe the skin of the test area dry with gauze or a clean towel before administration;

Dosing: Weigh the required amount of test sample and apply it evenly on the depilated area on the back of miniature pigs. The dosage and area of each animal are calculated based on the most recent weight. The dosage area = dosage / application volume.

The results showed that during the administration period, the pigs in each group were in good condition, with normal autonomous activities, no death or dying, and no other obvious toxic symptoms; the irritation score of the administration site of the pigs in each group was 0 points, no abnormal manifestations such as erythema and edema were observed, and there was no irritation to the skin at the administration site; there were no obvious abnormal changes in the weight and food intake of the pigs in each group; at the end of the administration, there were no obvious abnormal changes in the hematological indicators such as WBC and its classification counts and percentages, RBC, HGB, HCT, MCV, MCH, MCHC, PLT, RET, RET%, APTT, PT, etc.; the ALT, AST, ALP, LDH, GGT, UREA, There were no obvious abnormal changes in blood biochemical indicators such as CREA, CHOL, TP, ALB, GLB, TG, TBIL, CK, GLU, A/G, K+, Na+, and Cl-; there were no obvious abnormal changes in the weights of the brain, liver, kidney, adrenal gland, heart, spleen, thyroid gland, thymus/parathyroid gland, epididymis, testis, ovary, uterus/cervix, and visceral and visceral-brain coefficients of the pigs in each group; gross dissection and naked eye observation of the remaining organs or tissues of the pigs in each group showed no abnormal changes in size, shape, color, texture, etc. related to the test article; there were no abnormal histopathological changes in the skin and subcutaneous surrounding tissues at the administration site of the pigs in each group that were related to the test article.

Test Example 7: User Experience Comparison

Comparison of the skin use experience of the latex provided by the present disclosure (Example E2) and the hydrogel of the prior art (Comparative Example R2)

Test method:

This study was conducted in 10-20 healthy subjects to evaluate functional and cosmetic properties. The test products (Example E2, Comparative Example R2) were identified by blind identification codes, thereby preventing the test subjects from knowing the identity of the applied test products. The subjects were randomly applied on the left and right arms, respectively, and the age range of the subject group was between 20-40 years old.

The following properties were evaluated during and after application: ease of application, foreign body sensation during application, stickiness after application, odor, absorption rate after application, drying time of the skin, skin feel after application, overall cosmetic preference and usability of the product.

The results show that: all subjects said that the application experience of Example E2 and Comparative Example R2 was not much different, and generally reflected that Example E2 had the advantages of easy application, no foreign body feeling, no stickiness, no unpleasant odor, and fast absorption.

Claims (55)

A compound composition of adapalene and dapsone comprises, by total weight of the composition, 1%-15% of dapsone, 0.05%-0.5% of adapalene, 0.25%-20% of a carboxylic acid ester oily solvent, 0.5%-20% of a polyoxyethylene nonionic surfactant, 5%-50% of diethylene glycol monoethyl ether, and other pharmaceutically acceptable carriers. The composition according to claim 1, characterized in that, based on the total weight of the composition, the composition comprises 0.25-15% of a carboxylic acid ester oily solvent. The composition according to claim 2, characterized in that, based on the total weight of the composition, the composition comprises 0.25-5% of a carboxylic acid ester oily solvent. The composition according to claim 3, characterized in that, based on the total weight of the composition, the composition comprises 0.25-1% of a carboxylic acid ester oily solvent. The composition according to claim 1, characterized in that the carboxylate oily solvent is selected from any one of monocarboxylate, dicarboxylate, tricarboxylate or a mixture thereof. The composition according to claim 5, characterized in that the carboxylate oily solvent is a monocarboxylate oily solvent. The composition according to claim 5 or 6, characterized in that the monocarboxylic acid ester oily solvent is selected from any one of propylene glycol monocaprylate and propylene glycol monolaurate or a mixture thereof. The composition according to any one of claims 5 to 7, characterized in that the carboxylic acid ester oily solvent is propylene glycol monocaprylate. The composition according to claim 1, characterized in that, based on the total weight of the composition, the composition comprises 0.5-15% of a polyoxyethylene nonionic surfactant. The composition according to claim 9, characterized in that, based on the total weight of the composition, the composition comprises 0.5-10% of a polyoxyethylene nonionic surfactant. The composition according to claim 10, characterized in that, based on the total weight of the composition, the composition comprises 0.5-5% of a polyoxyethylene nonionic surfactant. The composition according to claim 1, characterized in that the polyoxyethylene nonionic surfactant is selected from any one of polyoxyethylene castor oil, fatty alcohol polyoxyethylene ether, polyol polyoxyethylene ether fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester and fatty amine polyoxyethylene ether or a mixture thereof. The composition according to claim 12, characterized in that the polyoxyethylene nonionic surfactant is selected from polyoxyethylene castor oil. The composition according to claim 13, characterized in that the polyoxyethylene nonionic surfactant is selected from any one of polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil or a mixture thereof. The composition according to claim 14, characterized in that the polyoxyethylene nonionic surfactant is polyoxyethylene 35 castor oil. The composition according to claim 1, characterized in that the composition comprises 10% to 50% of diethylene glycol monoethyl ether based on the total weight of the composition. The composition according to claim 16, characterized in that the composition comprises 15% to 45% of diethylene glycol monoethyl ether based on the total weight of the composition. The composition according to claim 17, characterized in that the composition comprises 30%-45% of diethylene glycol monoethyl ether based on the total weight of the composition. The composition according to claim 1, characterized in that, based on the total weight of the composition, the composition comprises 5%-10% of dapsone and 0.1%-0.3% of adapalene. The composition according to claim 19, characterized in that, based on the total weight of the composition, the composition comprises 7.5% of dapsone and 0.1% of adapalene. The composition according to claim 19, characterized in that, based on the total weight of the composition, the composition comprises 6% dapsone and 0.1% adapalene. The composition according to claim 19, characterized in that, based on the total weight of the composition, the composition comprises 5% dapsone and 0.1% adapalene. The composition according to claim 1, characterized in that the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent in the composition is ≥1:1 or >1:1. The composition according to claim 23 is characterized in that the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylic acid ester oily solvent in the composition is ≤3:1. The composition according to claim 1, characterized in that the other pharmaceutically acceptable carrier comprises a crystallization inhibitor, and the composition comprises 0.5%-4% of the crystallization inhibitor based on the total weight of the composition. The composition of claim 25, wherein the composition comprises 1% to 3% of a crystallization inhibitor based on the total weight of the composition. The composition according to claim 25, characterized in that the crystallization inhibitor is selected from any one or a combination of PVP, PVA and HPC. The composition according to claim 27, characterized in that the crystallization inhibitor is PVP. The composition according to claim 28, characterized in that the PVP is PVP-K30. The composition according to claim 1, characterized in that the pharmaceutically acceptable carrier further comprises a polymer copolymer emulsifier, and based on the total weight of the composition, the composition comprises 0.05-6% of the polymer copolymer emulsifier. The composition according to claim 30, characterized in that the composition comprises 0.05%-1% of the high molecular weight copolymer emulsifier based on the total weight of the composition. The composition according to claim 31, characterized in that the composition comprises 0.1%-0.5% of the high molecular weight copolymer emulsifier based on the total weight of the composition. The composition according to claim 30, characterized in that the polymer copolymer emulsifier is a carbomer copolymer. The composition according to claim 33 is characterized in that the carbomer copolymer is an acrylic acid (ester)/(C10-30) alkanol acrylate cross-linked copolymer. The composition according to claim 1, characterized in that the pharmaceutically acceptable carrier further comprises a thickener, and based on the total weight of the composition, the composition comprises 0.1%-4% of the thickener. The composition according to claim 35 is characterized in that the thickener is a combination of Sepineo P600 and Carbomer 981. The composition according to claim 36 is characterized in that, based on the total weight of the composition, the composition comprises 1%-3% Sepineo P600 and 0.1%-1% Carbomer 981. The composition according to claim 1, characterized in that the oil droplet diameter of the composition is ≤300 nm. The composition according to claim 1, characterized in that the composition is a latex. The composition according to claim 1, characterized in that the composition is an emulsion. The composition according to claim 1, characterized in that the pharmaceutically acceptable carrier further comprises any one or a combination of a preservative, an antioxidant, a chelating agent and a pH adjuster. The composition according to claim 41, characterized in that the preservative is methyl paraben. The composition according to claim 41, characterized in that the antioxidant is butylated hydroxytoluene. The composition according to claim 41, characterized in that the chelating agent is disodium edetate. The composition according to claim 41, characterized in that the pH adjuster is sodium hydroxide. The composition according to claim 1, characterized in that the pH range of the composition is between 5.0-7.0, preferably 5.0-6.5, more preferably 5.0-6.0. The method for preparing the composition according to any one of claims 1 to 46, characterized in that the preparation method comprises the following steps: 1) preparing an oil phase: adding dapsone and adapalene to a mixed solution of a carboxylic acid ester oily solvent, a polyoxyethylene nonionic surfactant and diethylene glycol monoethyl ether to form an oil phase; 2) preparing the aqueous phase: uniformly dispersing other pharmaceutically acceptable carriers in water and mixing them to form an aqueous phase; or directly using water as the aqueous phase; 3) Emulsification: Add the oil phase of step 1) to the water phase of step 2), adjust the pH to 5.0-6.0, mix well, and add water to 100%. Preferably, the other pharmaceutically acceptable carrier in step 2) is any one or a combination of a polymer emulsifier, a thickener and a crystallization inhibitor. Preferably, the other pharmaceutically acceptable carriers in step 2) are high molecular weight polymer emulsifiers, thickeners and crystallization inhibitors. Preferably, in step 2), a thickener may be added after adding the polymer copolymer emulsifier. Preferably, in step 2), a crystallization inhibitor may be added before adding the high molecular weight copolymer emulsifier. Preferably, any one or a combination of a penetration enhancer, an antioxidant, a preservative and a chelating agent may be added in step 1) or/and 2). Disclosed is a use of a compound composition of adapalene and dapsone in preparing a medicine for treating skin diseases. The use according to claim 48, characterized in that the skin disease is selected from acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, nodular prurigo and prickly heat. The use according to claim 48 or 49, characterized in that the skin disease is acne vulgaris. A use of a compound composition of adapalene and dapsone in preparing a pharmaceutical preparation for topical application. The use according to claim 51 is characterized in that the topically applied pharmaceutical preparation is selected from an emulsion, a latex or a cream. A method for treating skin diseases, comprising administering a therapeutically effective amount of the compound composition of adapalene and dapsone according to any one of claims 1 to 46 to a subject in need thereof. The method of claim 53, wherein the skin disease is selected from acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, and prickly heat. The method of claim 53 or 54, wherein the skin disease is acne vulgaris.